Novel KDM5B splice variants identified in patients with developmental disorders: Functional consequences

Lebrun, Nicolas; Mehler‐Jacob, Claire; Poirier, Karine; Zordan, Cécile; Lacombe, Didier; Carion, Nathalie; Billuart, Pierre; Bienvenu, Thierry

doi:10.1016/j.gene.2018.09.016

Cited by 27 publications

(21 citation statements)

References 21 publications

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“…Many of these cognitive and motor deficits are recapitulated in Kdm5c knockout mice, consistent with the evolutionary conservation of KDM5C's neuronal functions (Iwase et al, 2016;Scandaglia et al, 2017). Genome-wide studies of patients with ID and their families have also revealed a link between mutations in KDM5B and autosomal recessive cognitive impairment (Al-Mubarak et al, 2017;Faundes et al, 2018;Lebrun et al, 2018) (OMIM#618109). While examination of Kdm5b knockout mice firmly establishes a direct genetic link between loss of KDM5B and ID, the range and severity of patient phenotypes associated with these mutations are less defined than those associated with KDM5C-induced ID (Faundes et al, 2018;Martin et al, 2018).…”

Section: Introductionmentioning

confidence: 60%

“…These data suggest that ID-associated mutations that result in the loss of histone demethylase activity are likely to cause electrophysiological changes at glutamatergic synapses. Because at least half of the known ID-associated alleles in KDM5A, KDM5B and KDM5C are expected to reduce protein expression or stability (Brookes et al, 2015;Lebrun et al, 2018), many patients are expected to lack histone demethylase activity.…”

Section: Discussionmentioning

confidence: 99%

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The histone demethylase KDM5 is required for synaptic structure and function at theDrosophilaneuromuscular junction

Belálcazar

Hendricks

Zamurrad

et al. 2020

Preprint

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Mutations in the genes encoding the KDM5 family of histone demethylases are observed in individuals with intellectual disability (ID). Despite clear evidence linking KDM5 function to neurodevelopmental pathways, how this family of proteins impacts transcriptional programs to mediate synaptic structure and activity remains unclear. Using the Drosophila larval neuromuscular junction (NMJ), we show that KDM5 is required for neuroanatomical development and synaptic function. The JmjC-domain encoded histone demethylase activity of KDM5, which is expected to be diminished by many ID-associated alleles and required for appropriate synaptic morphology and neurotransmission. The C5HC2 zinc finger of KDM5 is also involved, as an ID-associated mutation in this motif reduces NMJ bouton number but increases bouton size. KDM5 therefore uses demethylase-dependent and independent mechanisms to regulate NMJ structure and activity, highlighting the complex nature by which this chromatin modifier carries out its neuronal gene regulatory programs.

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Section: Introductionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

The histone demethylase KDM5 is required for synaptic structure and function at theDrosophilaneuromuscular junction

Belálcazar

Hendricks

Zamurrad

et al. 2020

Preprint

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show abstract

“…Accordingly, we attributed the Chiari malformation to the variant in KDM5B whereas the one in BCORL1 was presumably responsible for the mild neurodevelopmental disorder of both kids, as reported in Shukla-Vernon syndrome (#301029). KDM5B, also known as JARID1B, has been associated with an autosomal recessive ID syndrome (#618109), whereas a gain of function mechanism (GoF) has been suggested for the heterozygous missense variants detected in ID patients, (Lebrun 2018). In our case, the variant is de novo and falls within the BRIGHT domain, which contributes to the recognition of the H3K4me2 substrate peptide (Johansson 2016), that suggests its pathogenetic role ( Supplementary Fig.…”

Section: W2 Histone Demethylasesmentioning

confidence: 72%

Chiari 1 malformation and exome sequencing in 51 trios: the emerging role of rare missense variants in chromatin-remodeling genes

et al. 2020

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Type 1 Chiari malformation (C1M) is characterized by cerebellar tonsillar herniation of 3–5 mm or more, the frequency of which is presumably much higher than one in 1000 births, as previously believed. Its etiology remains undefined, although a genetic basis is strongly supported by C1M presence in numerous genetic syndromes associated with different genes. Whole-exome sequencing (WES) in 51 between isolated and syndromic pediatric cases and their relatives was performed after confirmation of the defect by brain magnetic resonance image (MRI). Moreover, in all the cases showing an inherited candidate variant, brain MRI was performed in both parents and not only in the carrier one to investigate whether the defect segregated with the variant. More than half of the variants were Missense and belonged to the same chromatin-remodeling genes whose protein truncation variants are associated with severe neurodevelopmental syndromes. In the remaining cases, variants have been detected in genes with a role in cranial bone sutures, microcephaly, neural tube defects, and RASopathy. This study shows that the frequency of C1M is widely underestimated, in fact many of the variants, in particular those in the chromatin-remodeling genes, were inherited from a parent with C1M, either asymptomatic or with mild symptoms. In addition, C1M is a Mendelian trait, in most cases inherited as dominant. Finally, we demonstrate that modifications of the genes that regulate chromatin architecture can cause localized anatomical alterations, with symptoms of varying degrees.

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“…The demethylase activity of KDM5 is therefore needed for appropriate glutamatergic neurotransmission. Although this allele is not a patient-associated mutation, at least half of the known IDassociated variants in KDM5 family genes are expected to affect histone demethylase activity (Brookes et al, 2015;Lebrun et al, 2018). Thus, phenotypic analyses of this allele are likely to have implications for a number of patients.…”

Section: Discussionmentioning

confidence: 99%

The histone demethylase KDM5 is required for synaptic structure and function at the Drosophila neuromuscular junction

Belálcazar¹,

Hendricks²,

Zamurrad³

et al. 2021

Cell Reports

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Novel KDM5B splice variants identified in patients with developmental disorders: Functional consequences

Cited by 27 publications

References 21 publications

The histone demethylase KDM5 is required for synaptic structure and function at theDrosophilaneuromuscular junction

The histone demethylase KDM5 is required for synaptic structure and function at theDrosophilaneuromuscular junction

Chiari 1 malformation and exome sequencing in 51 trios: the emerging role of rare missense variants in chromatin-remodeling genes

The histone demethylase KDM5 is required for synaptic structure and function at the Drosophila neuromuscular junction

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